The present invention is directed to high energy phototherapeutic agents, or specifically to radiosensitizing and methods of treating and imaging using such phototherapeutic or radiosensitizer agents. More specifically, the treating and imaging is of diseased tissue, such as tumors, particularly cancerous tumors.
Diseased tissue or tumors, such as those for cancer, are often treated using ionizing radiation, in a process known as radiation therapy.
Radiation therapy (which typically uses electromagnetic radiation with energies of 1 keV or higher) for cancer typically works by attacking rapidly growing cells with highly penetrating ionizing radiation. Use of such radiation is attractive due to its ability to penetrate deeply into tissue, especially when diseased tissue is, or is located within, bone or other dense or opaque structures. Unfortunately, using rapid growth as the sole targeting criterion does not limit the effects of such treatment to cancer cells.
As a result, improvements have been made in the methods for delivery of the ionizing radiation to the site of the cancerous tumor so as to limit the effects of such radiation to the general area of the cancerous tumor. However, since healthy tissue and cancerous tissue typically have a similar biological response to radiation, a need exists to improve the potency of (or biological response to) the delivered radiation within and in the vicinity of the tumor, while not affecting the surrounding healthy tissue.
As an alternative to the use of ionizing radiation, photodynamic therapy (PDI) has been developed and shows considerable promise for treatment of a variety of cancers. Photodynamic therapy is the combination of a photosensitive agent with site-specific illumination (using non-ionizing, optical radiation) to produce a therapeutic response in diseased tissue, such as a tumor. In PDT, a preferential concentration of photosensitizer is to be located in the diseased tissue, either through natural processes or via localized application, and not in the healthy surrounding tissue. This provides an additional level of tissue specificity relative to that achievable through standard radiation therapy since PDT is effective only when a photosensitizer is present in tissue. As a result, damage to surrounding, healthy tissue can be avoided by controlling the distribution of agent. Unfortunately, when using conventional methods for the illumination step in PDT (1) the light required for such treatment is unable to penetrate deeply into tissue, and (2) the physician has minimal spatial control of the treatment site. This is particularly troublesome whenever the diseased tissue or tumor is deeply seated or located within bone or other opaque structures. Some of the inventors of the present invention have been able to resolve many of these problems for PDT, as shown in commonly-assigned U.S. Pat. No. 5,829,448.
Others, however, have focused their efforts on developing agents that are sensitized or activated by the ionizing radiation mentioned above. Potentially, the use of such radiation would enable treatment of more deeply seated diseased tissue than that possible with optical radiation. The agents used with such radiation are known as radiosensitizers. It is also desirable to achieve preferential concentration of the radiosensitizer in the diseased tissue, either through natural processes or via localized application, so as to provide additional specificity relative to that achievable through standard radiation therapy. The desired result is for radiation to become more efficacious when the radiosensitizer is present in tissue, so that less radiation is needed to treat the lesion tumor or other diseased tissue, and accordingly, potential damage to surrounding healthy tissue, resulting from collateral exposure to the radiation, is reduced. Hence, safety and efficacy would then be improved.
The ultimate success or failure of the radiosensitizer approach depends on: (1) therapeutic performance of agents, and (2) disease specificity in the site of activation. Currently used agents and targeting approaches, however, have had unacceptable results in each of these categories.
The therapeutic performance of a radiosensitizer is primarily a function of enhanced absorption of the applied radiation dose in sensitized tissues relative to that in non-sensitized tissues. This differential absorption is commonly effected by use of agents having a high absorption cross-section for a particular type of radiation (such as x-rays). For example, metal or halogen atoms are often used, either in atomic form or incorporated into a molecular carrier, due to their high x-ray cross-section. Absorption of x-rays by such atoms appears to lead to secondary radiative emissions, ionization, and other chemical or physical processes that increase the localized cytotoxicity of the applied energy (i.e., radiation-induced cell death, or "light cytotoxicity").
However, a high light cytotoxicity is not enough to make an agent an acceptable agent. The agents must also have a negligible effect when energy is not applied (i.e., have a low toxicity in the absence of radiation, or "dark cytotoxicity"). Unfortunately, many agents presently under investigation as radiosensitizers have the disadvantage of either: (a) a relatively high dark cytotoxicity or (b) a low light (cytotoxicity)-to-dark cytotoxicity ratio which limits their effectiveness and acceptability. Agents having a high light-to-dark cytotoxicity ratio are desirable because they (1) can be safely used over a range of dosages, (2) will exhibit improved efficacy at the treatment site (due to the compatibility with use at higher dosages as a consequence of their relative safety), and (3) will be better tolerated throughout the patient's body.
An additional problem with many current radiosensitizers is that the agent does not achieve significant preferential concentration in tumors. Specifically, most radiosensitizer targeting has been based on physical targeting, such as diffusion into tumors through leaky neurovasculature, which ultimately succeed or fail based on permeability of the tumor to agents that are aqueously soluble or are in a suspension formulation. As a result, large doses of the agent typically need to be administered, either locally or systemically, so as to saturate all tissues, hopefully reaching a therapeutic level in the desired treatment region or target. After such agent administration, a patient has to wait a clearance time of hours to days to allow excess agent to hopefully clear from healthy living tissues surrounding the desired treatment site. Thereafter, irradiation of residual agent at the treatment site hopefully produces the desired cytotoxic effect in the diseased tissue. This approach may unfortunately also damage healthy surrounding tissue by undesired but unavoidable activation of residual agent still present in the healthy surrounding tissue. One approach to solving this problem is to couple the radiosensitizer with a moiety capable of providing improved biotargetting of the diseased tissue. This, however, has proven to be very difficult to achieve.
It would also be highly desirable if the radiosensitizer could be used to improve identification of target size, location and depth so that the therapeutic radiation could be more precisely delivered to the target, such as a cancerous tumor. Combined diagnostic use (as a contrast agent) and therapeutic use (as a radiosensitizer) of the agent would reduce risk to the patient by (1) reducing the number of required procedures necessary for diagnosis and treatment, (2) reducing the overall diagnosis and treatment time, and (3) reducing cost.
Accordingly, one object of the present invention is to develop new radiosensitizers that have one or more of the following characteristics: (1) improved light-to-dark cytotoxicity ratio; (2) improved accumulation of agent into diseased tissue with strong contrast between diseased and healthy tissue; (3) rapid clearance from normal tissue; and (4) capability of combined imaging and therapy. Further desirable characteristics include low agent cost, and significant regulatory history (so as to facilitate acceptance by the regulatory and medical communities).